Outline

Introduction: NK cells play a paradoxical role in alloresponses and have recently been shown to have phenotypic features of CD11c+ dendritic cells (DCs). Our latest data show that such NK-dendritic cells (NKDCs) play a dichotomous role in regulating CD4+ T cell responses, contingent on their activation status. However, the precise factors that regulate such attributes in NK cells and their significance in CD8+ T cell responses are unknown.

Materials and methods: To examine the DC-like phenotypic and functional features of CD3-NK1.1+ NK cells, we created homozygous B6.CD11c-GFP reporter mice, in which the expression of CD11c is genetically linked to co-expression of GFP and diphtheria toxin receptor. Furthermore, we used CD8-TCR-transgeneic B6.OTI-Foxp3-GFP-knockin mice, in which Foxp3-expression is linked to GFP-co-expression, to study the role of NKDCs as APCs in CD8+ T effector and regulatory cell responses.

Results: Using a polychromatic approach we confirmed that NK cells in wt B6 and B6.CD11c-GFP mice express DC-relevant markers such as CD11c, B220, CD86, and MHCII. Thus, we hypothesized that NKDCs by themselves may directly function as APCs that regulate antigen-specific CD8+ T cell responses in vitro. Using our OTI-Foxp3 GFP-knockin model, we found that NKDCs induce robust proliferation of CD8+GFP- T effector cells (Teffs) at levels comparable to B cells but fail to generate CD8+Foxp3+ regulatory T cells (CD8+ Tregs) under Tregs-polarizing conditions. Importantly, we also found that NKDCs, when compared to B cells, pDCs, and conventional DCs, are powerful inducers of zytopathic CD8+GFP- T17 cells in the presence of IL-6 and TGF-β; In line with this, wt CD8+ T cells were required for rejection of heterotopic Balb/c heart transplants by B6.Rag KO mice in an adoptive transfer model.

Conclusion: Thus, NKDCs may play a critical role in regulating CD8+ T cell responses, giving them a novel role in directly regulating peripheral T cell homeostasis in transplantation.